High linear energy transfer (LET) radiations are important to human health since some 40,000 workers in the US are at risk each year for exposures to low-energy neutrons. Also, there is considerable public concern over possible exposures to alpha particles emitted by radon gases. Estimations of the relative biological effectiveness (RBE) of such high-LET radiations are typically made by calculating the ratios of doses in Gy that yield the same level of biological effect as X- or gamma-rays. However, at the level of the cell target, the harmful effects of ionizing radiation do not depend on radiation "dose" in the classical sense, but more precisely, on the spatial and temporal distributions of ionizations within critical target sites at the nanometer level. Thus, to understand the mechanisms by which radiations of differing LET cause damage to biologically important molecules, effects must be studied at the single cell level for radiations having well defined LET. To characterize the effects of high-LET radiations in inducing relevant genomic damage in human somatic cells, we will evaluate chromosome aberrations in lymphocytes exposed to track segment radiations of narrowly defined LET. We will use a novel approach to irradiate single-cell layers with high-LET accelerated particles produced by the van de Graaff accelerator at RARAF. Chromosome damage will be quantified using classical methods, and by state-of- the-art techniques using fluorescence in situ hybridization with chromosome-specific "painting probes". In addition to studying the spectrum of aberrations induced as a function of radiation dose in cGy, we will characterize the effects of radiation of each LET on the basis of damage induced on a per track per cell basis. For selected LETs, we will also conduct studies to determine the extent to which dimethyl sulfoxide and WR-1065 protect against damage induced by radiations of differing LET. Our objectives are to produce a detailed profile of radiation- induced damage at the single-cell level in a human cell type in relation to the spatial and temporal distributions of ionizing clusters deposited within critical DNA targets, and to derive precise estimates of the relative biological effectiveness of high- LET radiations at the level of the cell.